Mechanistic Insight into Self-Gelation Involved in Prescription Design for Optimization of Tablet Performance

Abstract

Some drugs undergo gelation during the formulation development process, which not only poses significant challenges to the manufacturing process of solid dosage forms but also significantly restricts the drug dissolution and absorption. Could such gelation be utilized by designing the prescription to overcome the adverse effects and water solubility defect of drugs? Herein, this study attempted to design the self-gelation tablets of indomethacin (IND) by introducing small-molecule ligands and to explore the self-gelation mechanism. As a result, the designed tablets occurred to have spontaneous gelation with a typical 3D structure and viscoelasticity upon contact with a small amount of water, accompanied by amorphization transformation. Such a self-gelation behavior was significantly influenced by the composition ratios, storage temperatures, and medium pH values. In comparison to pure IND tablet, the designed IND-ligand tablets performed significantly increased apparent solubility (>200-fold) and intrinsic dissolution rate (>6000-fold) and maintained the long-term supersaturated dissolution with acid–base interactions, which was revealed by nucleation inhibition, fluorescence quenching, and phase solubility tests. Moreover, the self-gelled tablets significantly enhanced the membrane permeability of IND, demonstrating the potential for promoting oral absorption. Thus, this study revealed the self-gelation mechanism of the tablet combination and confirmed such prescription design involving self-gelation as an efficient solubilization strategy.